2025-03-05 長崎大学,理化学研究所,北海道大学
<関連情報>
- https://www.riken.jp/press/2025/20250305_2/index.html
- https://www.nagasaki-u.ac.jp/ja/guidance/kouhou/press/pdf/748file1_20250305114108.pdf
- https://www.sciencedirect.com/science/article/pii/S0168365925001774
S.typhimuriumのVNP20009投与による腫瘍間質の開口により、リポソーム抗がん剤による難治性腫瘍の完全な増殖抑制が可能になる Tumor-stromal opening via S. typhimurium VNP20009 administration for complete inhibition of refractory tumor growth with liposomal anticancer drugs
Akari Kato, Shoko Nomura, Maiko Takahashi, Erike Widyasari Sukowati, Hideyoshi Harashima, Hidefumi Mukai
Journal of Controlled Release Available online: 22 February 2025
DOI:https://doi.org/10.1016/j.jconrel.2025.02.064
Graphical abstract
Hightlights
- S. typhimurium VNP20009 drastically improved the liposomal tumor distribution.
- Tumor vascular structure collapsed accompanied by VNP20009 administration.
- The combination of VNP20009 and liposomal anticancer drugs completely cured tumors.
- VNP20009 can act as a tumor stromal opening agent for liposomal anticancer drugs.
Abstract
Many clinical tumors exhibit a vascular endothelium covered by mural cells and stroma with abundant collagen fibers, which greatly inhibit the penetration of nanoparticle drug delivery systems (DDS) formulations deep into the tumors. We previously found that Salmonella typhimurium VNP20009 attracting attention as live bacterial therapeutics, which is a novel pharmaceutical modality for cancer treatment, can grow within deep tumors with abundant stroma and tight vasculature. Because this finding interestingly indicates that VNP20009 administration disrupts vascular and stromal structures even in refractory tumors, we investigated the possibility that VNP20009 administration improves DDS formulations migrations into tumors in this study. VNP20009 co-administration drastically improved the translocation and diffusion of liposomes deep into the tumors, particularly in stroma-rich xenografted tumors, indicating its tumor stromal opening ability. Furthermore, this approach can completely inhibit tumors in various refractory tumor models, including pancreatic cancers, using liposomal doxorubicin (Doxil®) and liposomal irinotecan (Onivyde®). Notably, this remarkable anticancer effect is not simply attributed to the therapeutic effects of liposomal anticancer drugs and VNP20009, but it involves an additional effect, improving the intratumor pharmacokinetics of liposomal anticancer drugs following VNP20009 co-administration. The unique tumor stromal opening ability of VNP20009 demonstrated in this study is a promising strategy for resolving the major challenges faced by tumor DDS.
